Methods and systems for toxin delivery to the nasal cavity

ABSTRACT

Methods and systems for delivering toxin and toxin fragments to a patient&#39;s nasal cavity provide for both release of the toxin and delivery of energy which selectively porates target cells to enhance uptake of the toxin. The use of energy-mediated delivery is particularly advantageous with light chain fragment toxins which lack cell binding capacity.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/139,710 filed Dec. 23, 2013 which is a continuation ofapplication Ser. No. 13/328,203, filed on Dec. 16, 2011, which is acontinuation of application Ser. No. 12/636,477, filed on Dec. 11, 2009,which is a divisional of application Ser. No. 11/750,963, filed on May18, 2007, which is a continuation-in-part of application Ser. No.11/459,090, filed on Jul. 21, 2006, which claimed the benefit ofprovisional application No. 60/702,077, filed on Jul. 22, 2005, and ofprovisional application No. 60/747,771, filed on May 19, 2006; the fulldisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical methods and systems.More particularly, the present invention relates to methods and systemsfor delivering toxins, such as botulinum toxin light chain fragments, totarget cells in a nasal cavity.

Rhinitis, which includes the symptoms of rhinorrhea, is a conditionresulting from inflammation and swelling of the patient's mucusmembranes which line the nasal cavity. Rhinitis and/or rhinorrea canarise from a number of conditions, most often results from allergies topollen, dust, seasonal allergens or other airborne substances, but canalso be caused by anatomic pathologies such as blockages (as in the caseof sinusitis). Symptoms may include sneezing, itching, nasal congestion,and a runny nose.

While numerous treatments for rhinitis have been proposed over theyears, no single treatment is optimum for all patients or allconditions. Most commonly, hay fever and other forms of rhinitis aretreated with antihistamines which block the inflammatory response. Whileeffective, many antihistamines can cause drowsiness, have a limitedduration of effect, and present the patient with an on-going cost tocontinuously purchase the drugs.

Recently, a longer term therapy for rhinitis which relies on the use ofbotulinum toxin (“BoNT”) for blocking mucus production bymucus-producing cells in the nasal membrane has been proposed. Botulinumand other neurotoxins are capable of disabling adrenergic cells,including epithelial or goblet cells which are responsible for themajority of mucus production in the nasal cavity membrane. Dr. IraSanders has demonstrated that introduction of intact botulinum toxinmolecules into the nasal passages of canines can reduce mucus secretionby a significant amount.

While the experimental work of Dr. Sanders holds promise for long termrhinitis treatment, it faces a number of challenges before it issuitable for wide spread use in humans. In particular, botulinum toxinis a neurotoxin which could have significant negative effects on apatient if accidentally released outside of the targeted nasal passages.Inadvertent distribution of the toxin to muscles of the oropharynx,mouth, tongue, or elsewhere could result in serious complications to thepatient. Additionally, the use of botulinum-soaked gauze pads fordelivering the toxin to the nasal cavities, as demonstrated by Dr.Sanders, will have limited ability to uniformly and selectively deliverthe botulinum to the regions having high concentrations of preferredtarget cells, such as epithelial or goblet cells in the nasopharynx.

For these reasons, it would be desirable to provide improved methods andsystems for delivering toxins, such as botulinum and active botulinumfragments, to the nasal membrane of a patient, particularly a patientsuffering from rhinitis or other conditions associated with nasalinflammation and conditions, such as sinus headaches and migraineheadaches. The methods and systems should be capable of providing forselective and repeatable delivery of the toxins to defined target areaswithin the nasal cavities, including particular paranasal sinuses, thenasopharynx, and in some cases substantially the entire nasal cavity.The systems and methods should provide for the safe and effectivedelivery of the toxins, and in particular should reduce or eliminate therisk of toxin being delivered to non-targeted tissues outside of thenasal cavity. At least some of these objectives will be met by theinventions described herein below.

2. Description of the Background Art

U.S. Pat. No. 5,766,605, to Sanders et al. has been described above.Sharri et al. (1995) Otolaryngol. Head Neck Surg. 112: 566-571 alsoreports the work of Dr. Sanders described in the '605 patent. Ünal etal. (2002) Acta Otolaryngol 123: 1060-1063 describes the injection ofbotulinum toxin A into the turbinates of patients suffering fromallergic rhinitis. See also, U.S. Pat. No. 6,974,578. The purificationand possible therapeutic uses of botulinum light chain are described inUS2004/0151741, US2005/0019346, and Chaddock et al. (2002) ProteinExpression and Purification 25: 219-228. Energy-mediated transdermaldelivery of intact botulinum toxin is suggested in US2005/007441 and2004/0009180. The use of catheters and other devices for theenergy-mediated delivery of botulinum light chain is described incommonly owned co-pending provisional application 60/702,077, filed Jul.22, 2005, the full disclosure of which has previously been incorporatedherein by reference.

BRIEF SUMMARY OF THE INVENTION

The present invention provides treatments for any disease or conditionfor which rhinorrhea is a result or symptom.

Rhinorrhea is the term describing the effluence of mucus from the liningof the nasal passages, nasopharynx, or paranasal sinuses. Rhinorrhea canbe a symptom of a number of diseases such as the common cold, sinusitisor rhinitis, Rhinitis (inflammation of the airways) falls into two majorcategories—allergic and non-allergic (or vasomotor) rhinitis. Each canhave several subcategories. Sinusitis is an infection or inflammation ofthe paranasal sinuses. Sinusitis may have a number of different causes,and can be the result of chronic inflammation of the nasal passages, forexample as a result of chronic rhinitis.

Allergic rhinitis is an immunologic response modulated by IgE andcharacterized predominantly by sneezing, rhinorrhea, nasal congestion,and pruritus of the nose. It may be seasonal (a condition commonlyreferred to as hay fever) or perennial. The seasonal form is caused byallergens released during tree, grass, or weed pollination, whereas theperennial form is caused by allergies to animal dander, dust mites, ormold spores with or without associated pollinosis. Data also suggestthat urban air pollutants from automobiles and other sources may have anadjunctive effect.

Nonallergic rhinitis is a diagnosis of rhinitis without anyimmunoglobulin E (IgE) mediation, as documented by allergen skintesting. Hence, the rhinorrhea, sneezing, pruritus, and congestion donot result from allergy or hypersensitivity and continue to persist,whether continuously or sporadically. Nonallergic rhinitis affects 5-10%of the population. Nonallergic rhinitis has 7 basic subclassifications,including infectious rhinitis, nonallergic rhinitis with eosinophiliasyndrome (NARES), occupational rhinitis, hormonal rhinitis, drug-inducedrhinitis, gustatory rhinitis, and vasomotor rhinitis. Patients may ormay not present with the same symptoms seen in allergic rhinitis.

According to the present invention, botulinum toxin, ricin, exotoxin A,diphtheria toxin, cholera toxin, tetanus toxin, other neurotoxins, andactive fragments thereof are delivered to a patient's nasal membranewhile applying energy to target cells within the membrane underconditions which cause a reversible (or in some instancesnon-reversible) poration of the cell membranes to enhance delivery ofthe toxin into the cells. The region where the toxin is introduced maycomprise any portion of the nasal cavity, such as a single paranasalsinus or portion thereof, a main nasal passage, two or more paranasalsinuses, or in some cases may comprise substantially the entire nasalcavity of the patient. A particular target region for the toxin maycomprise the nasopharynx which is at the back of the nasal passage. Thenasopharynx comprises a cluster of epithelial or goblet cells which areresponsible for mucus secretion and which are susceptible to thedisabling mechanism of the botulinum toxin and other neurotoxins.

The energy is preferably selectively applied to a targeted regioncontaining a variety of cell types, including goblet cells, epithelialcells, ciliated and non-ciliated columnar cells, basal cells, and lessor no energy applied to untargeted regions. It will be appreciated thatthe energy may be applied to regions of the nasal membrane which are thesame or different from the regions to which the toxin has beenintroduced. By controlling the delivery area of both the toxin deliveryand the energy delivery, the methods and apparatus of the presentinvention can more specifically target the epithelial or goblet andother recipient cells of interest while minimizing the amount of toxinwhich enters non-targeted cells. That is, only those cells in the nasalmembrane which are exposed to both the toxin and the applied energy willpreferentially be permeablized or porated to receive the toxin withinthe cytoplasm of the cell.

The toxin to be delivered may comprise any neurotoxin capable ofdisabling mucus secretion in epithelial or goblet cells and othermucus-producing nasal cells. Preferably, the toxin comprises botulinumtoxin, although other toxins such as ricin, exotoxin A, diphtheriatoxin, cholera toxin, tetanus toxin, other neurotoxins, and activefragments thereof may also find use. In preferred aspects of the presentinvention, only an active fragment of the toxin will be delivered to thenasal cavity. Botulinum toxin and the other toxins listed above commonlycomprise both a heavy chain and a light chain. The heavy chain isresponsible for binding to the target cells and mediating passage of thelight chain into the cytoplasm of the target cells. By delivering onlythe light or active chain of these toxins (after removal of the heavychain or recombinant production of only the light chain), the risk ofaccidental delivery of the toxin to non-target cells is greatly reduced.Delivery of the active or light chain fragments into the target cells,according to the present invention, is mediated and enhanced by theselective application of an energy which porates the cell membrane toallow entry of the light chain or active fragment. The presentlypreferred botulinum light chain fragment may be derived from any one ofthe seven presently known botulinum types A-G.

Any type of energy which is capable of reversibly permeablizing orporating the cell wall to allow passage of the toxin molecule, eitherwhole toxin or preferably light chain fragment, into the cell cytoplasmmay be applied to the cell membrane. Thus, energy may comprise variousforms of electrical pulses, acoustic pulses, X-ray energy, microwaveenergy, or the like, and combinations thereof. Preferably, the energywill be either pulsed electrical energy of the type which is commonlyused for cellular electroporation or will be ultrasonic energy of thetype commonly employed for sonoporation of cells. The energy may beapplied using the same catheters or other structures which are used fordelivering the toxins. Alternatively, the energy may be applied usingseparate external or internal sources, such as using separate externalultrasonic transducers and/or ultrasound wave guides capable ofdelivering focused or unfocused ultrasound into the target tissues ofthe nasal cavity.

In specific embodiments of the methods of the present invention, thetoxin may be introduced to the target region through a catheter. Forexample, the catheter may carry a balloon which engages the nasalmembrane in order to effect delivery of the toxin to the target cells.In a particular example, the balloon is porous over at least a portionof its area so that the toxin may be released to specific areas of thenasal membrane, typically being incorporated into a suitable liquid,gel, or other fluid or fluidizable carrier. In other embodiments, thetoxin may be introduced through one or more needles carried on thecatheter, and in still other embodiments the toxin may be aerosolizedfrom a small port, nozzle, or other orifice or structure on thecatheter.

While the energy may be applied from a separate external source, asgenerally described above, the energy will most often be applied fromthe same catheter or other apparatus used to deliver the toxin. Forexample, when ultrasonic or other acoustic energy is being applied, thetransducer may be on or associated with the catheter. In a particularexample, it is shown that the transducer may be located within orbeneath the porous balloon which is used to deliver toxin to the nasalmembrane. When electrical energy is used for poration, the electrodesmay be on the catheter within or surrounding the region which deliversthe energy to the nasal membrane. In other instances, the energy may beapplied from a separate catheter or other device adapted for intranasalintroduction. In still other instances, the energy application willapply energy transcutaneously, for example from the skin of the face,typically surrounding the nose over the sinus cavities.

In addition to the methods described above, the present inventionfurther provides systems for delivering toxins to epithelial or gobletand other target cells as defined above in a nasal membrane. The systemsmay typically comprise a catheter adapted to introduce a toxin to aregion adjacent to the target cells. An energy applicator is furtherprovided for applying energy to the target cells under conditions whichcause a reversible poration of the cell membranes to enhance delivery ofthe toxin. Systems may still further comprise a source of the toxinsuitable for introduction from or through the catheter. The energyapplicator may be mounted on or incorporated within the catheter, or maybe a separate or external source. In an exemplary embodiment, asillustrated in FIG. 18, an external applicator may comprise a mask orother structure which fits over the nose and/or sinus region of thepatient and which is capable of delivering acoustic or microwave energyto the target cells within the target regions.

When the energy applicator is incorporated with or within the catheter,the delivery pattern of the energy will usually be at least partiallyoverlapping with the toxin delivery pattern of the catheter. Forexample, when a porous balloon is used for toxin delivery, the acoustictransducer, electroporation electrodes, or the like, will usually bedisposed to deliver energy which at least partly overlaps with thedispersion pattern of the toxin. In some instances, the region ofapplied energy will be coextensive with the region of toxin dispersion.In other instances, the two regions will only partially overlap. In thelatter case, the delivery of the toxin will be enabled or enhancedprincipally within the regions of overlap.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a schematic of the creation of neurotoxin Botulinum ToxinType A (BoNT/A), including the light chain (LC) fragment or portion.

FIG. 2A depicts a schematic of a target cell, including the cellmembrane, and inner cellular matrices.

FIG. 2B depicts a schematic of the target cell wherein LC molecule hasbeen introduced.

FIGS. 3A-3B depicts a the target cell of FIG. 2 showing application ofan energy field (EF) to produce permeabilization or pores (P) in thecell membrane, and introduction of the LC fragment therethrough.

FIG. 4 depicts a schematic of a cell wherein the energy field has beendiscontinued, and neurotransmission of the cell has been effectivelyblocked.

FIGS. 5, 5A-5B depicts various embodiments of a delivery device of thepresent invention utilizing multiple energy transmission elements and anenergy transmission system.

FIGS. 6A-6D, 6AA and 6CC depict various electrode catheterconfigurations adapted to deliver energy or energy and therapeuticagents to target tissue.

FIG. 7 depicts an embodiment of the present invention utilizing anultrasound element on a catheter device.

FIG. 8 depicts an embodiment of the present invention utilizing anaerosolizing element.

FIG. 9 depicts use on an external hand held transducer for enhancingcellular uptake of toxin delivered from a separate nasal aerosolizer.

FIGS. 10 and 11 depicts depict use of balloon catheters for deliveringtoxin to the nasopharynx.

FIGS. 12A-12C depict use of a self-expanding toxin delivery structure ona catheter.

FIGS. 13 and 14 depict a protocol for limiting toxin introduction bypartial filling of a porous delivery balloon.

FIG. 15 depicts sizing of a delivery balloon to control distribution oftoxin released into the nasal cavity.

FIG. 16 depicts placement of a delivery balloon to protect the olfactorybulb.

FIG. 17 depicts the use of multiple small balloons for selective toxindelivery into the nasal cavity.

FIG. 18 depicts sonoporation using an external mask placed over thesinuses and nose.

FIG. 19 depicts a front view of an external sonoporation mask showingplacement of ultrasound transducers.

FIGS. 20 and 21 depict an orally-introduced occlusion catheter andenergy applicator system.

FIGS. 22 and 23 depict nose plugs for occluding and optionally deliveryporation energy to the nasal cavity.

FIGS. 24 and 25 depict an alternate occlusion catheter system fortargeted toxin delivery to the nasopharynx.

FIGS. 26 and 27 depict use of a toxin delivery catheter having sideholes and a distal occlusion balloon for isolating and protecting theolefactory bulb.

FIGS. 28 and 30 depict use of a simple catheter having a shaped distalend for aerosolizing a toxin into a target nasal sinus though an ostiumopen to the sinus.

FIG. 29 depicts toxin delivery using a nasal spray and energy deliveryusing a face mask.

FIGS. 31 and 32 depict use of a catheter having a shaped distal end forpositioning separate infusion structures with a target sinus cavity.

FIG. 33 depicts an applicator device for delivering toxin to the nasalcavity having a handle and two applicator tips for placement within thenasal passageway.

FIG. 34 depicts a top view of the applicator device illustrated in FIG.33.

FIG. 35 depicts the applicator device illustrated in FIG. 33 when placedwithin the nasal passageway.

FIG. 36 depicts an applicator device configured with an infusion channeland access port for infusing solution to the applicator tip.

FIGS. 37A-37C depict the handle of an applicator device in an isometricview, a top view in an expanded state and a top view in a compressedstate, respectively.

FIG. 38 depicts an applicator device comprising a spring element.

FIGS. 39A-39B depict a sponge applicator tip for an applicator device ina dry low volume configuration and a wet expanded configuration,respectively.

FIGS. 40A-40B depict an applicator tip comprising a spring element in anexpanded configuration and a compressed configuration, respectively.

FIG. 41 depicts an applicator device comprising loop spring element.

FIG. 42 depicts a spring-loaded applicator tip held in a compressedstate by an engaged actuator.

FIG. 43 depicts an applicator device with the actuators of bothapplicator tips engaged by an engagement element.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and systems for deliveringtoxins to target cells within a patient's nasal cavity. The toxins maybe intact toxins, such as botulinum toxin, ricin, exotoxin A, diphtheriatoxin, cholera toxin, tetanus toxin, other neurotoxins, and activefragments thereof. Each of these toxins comprises a heavy chainresponsible for cell binding and a light chain having enzyme activityresponsible for cell toxicity.

Botulinum toxin blocks acetylcholine release from cells, such as theepithelial or goblet cells in the nasal membranes responsible for mucushypersecretion, and can thus be effective even without energy-mediateddelivery in accordance with the principles of the present invention. Theuse of energy to permeablize or porate the cell membranes of theepithelial or goblet cells or other mucus-secreting cells of the nasallining, in accordance with the present invention, allows botulinum andother toxins to be preferentially delivered to the targeted epithelialor goblet and other mucus-producing cells. Additionally, it allows useof the active or light chains of these toxins (having the heavy chainsremoved or inactivated) for treatments in accordance with the presentinvention. Normally, the light chains when separated from thecell-binding heavy chains of botulinum and the other toxins areincapable of entering the cells and thus will be free from significantcell toxicity. By using the energy-mediated protocols of the presentinvention, the toxin light chains may be locally and specificallyintroduced into the target cells located within defined regions of thenasal membrane. Thus, even if the toxin fragments are accidentallydispersed beyond the desired target regions, the fragments will notgenerally enter cells without the additional application of cellpermeablizing or porating energy. For that reason, the toxin deliverymethods of the present invention are particularly safe when performedwith toxin fragments, such as the light chain of botulinum and othertoxins.

While the remaining portion of this disclosure will be presented withspecific reference to the botulinum toxin light chain, it will beappreciated that the energy-mediated delivery protocols and systems mayalso be used with other intact toxins and in particular with other lightchain toxin fragments as just discussed.

Generally, the botulinum toxin molecule (BoNT) is synthesized as asingle polypeptide chain of 150 kD molecular weight. The neurotoxin isthen exposed to enzymes, either during cultivation of the Clostridiumbotulinum organism or subsequent to purification of the toxin, whereinspecific peptide bonds are cleaved or “nicked” resulting in theformation of a dichain molecule referred to as BoNT. As shown in FIG. 1,dichain neurotoxin is composed of a light chain region 50 kD molecularweight linked by disulfide bonds to a heavy chain 100 kD molecularweight (Kistner, A., Habermann, E. (1992) Naunyn Schmiedebergs Arch.Pharmacol. 345, 227-334). When the light chain is separated from theheavy chains of botulinum toxin, neither chain is capable of blockingneurotransmitter release, however, the light chain alone is capable ofblocking acetylcholine release if transported directly into the cellcytosol. (Ahnert-Hilger, G., Bader, M. F., Bhakdi, S., Gratzl, M. (1989)J. Neurochem. 52, 1751-1758 and Simpson, L. L. (1981) Pharmacol. Rev.33, 155-188.) Focusing on the light chain, the isolation or separationprocess essentially renders the light chain “non-toxic” in a generalenvironment, while still maintaining its effect or toxicity, once it istransported through the target cell membrane.

Over the past several years, the separation and purification of thelight chain and heavy chain of BoNT has seen significant developmentactivity. In the case of the heavy chain (HC), researchers areinterested in its ability to bond with a target cell and deliver certainmolecules into that cell. For example, various drug deliveryapplications have been suggested, for example, using the HC to bind totPA so that a patient could inhale the HC-bound tPA allowing it to crossthe membrane of the lungs and be transported into the bloodstream foranticoagulation. Of particular interest to the present invention are theefforts to isolate and purify the light chain (LC) of the botulinummolecule. In its isolated and purified form, all HC elements areremoved, rendering the LC incapable of crossing the cell membranewithout assistance. This renders the LC a non-toxic protein to the cellenvironment, while still maintaining its encoded toxicity by, once it iseffectively delivered to its appropriate catalytic environment; the cellcytosol.

Various groups have been active in the area of isolation andpurification. For example, companies such as Metabiologics, a groupaffiliated with the University of Wisconsin, the Center for AppliedMicrobiology and Research (CAMR), a division of the UK Health ProtectionAgency, List Biological Laboratories, Inc. of California, and otherresearch groups throughout the world. Many of these companies providepurified preparations of botulinum neurotoxins from Clostridiumbotulinum types A and B. List Laboratories in particular providesrecombinantly produced light chains from both types A, B, C, D and E.

For purposes of this specification, the terms “poration” and/or“permeablization” include various forms of electrically-medicatedporation, such as the use of pulsed electric fields (PEFs), nanosecondpulsed electric fields (nsPEFs), ionophoreseis, electrophoresis,electropermeabilization, as well as other energy mediatedpermeabilization, including sonoporation (mediated by ultrasonic orother acoustic energy), and/or combinations thereof, to create temporarypores in a targeted cell membrane. Similarly, the term “electrode” or“energy source” used herein, encompasses the use of various types ofenergy producing devices, including x-ray, radiofrequency (RF), DCcurrent, AC current, microwave, ultrasound, adapted and applied inranges to produce membrane permeabilization in the targeted cell.

Reversible electroporation, first observed in the early 1970's, has beenused extensively in medicine and biology to transfer chemicals, drugs,genes and other molecules into targeted cells for a variety of purposessuch as electrochemotherapy, gene transfer, transdermal drug delivery,vaccines, and the like.

In general, electroporation may be achieved utilizing a device adaptedto activate an electrode set or series of electrodes to produce anelectric field. Such a field can be generated in a bipolar or monopolarelectrode configuration. When applied to cells, depending on theduration and strength of the applied pulses, this field operates toincrease the permeabilization of the cell membrane and reversibly openthe cell membrane for a short period of time by causing pores to form inthe cell lipid bilayer allowing entry of various therapeutic elements ormolecules, after which, when energy application ceases, the poresspontaneously close without killing the cell after a certain time delay.As characterized by Weaver, Electroporation: A General Phenomenon forManipulating Cells and Tissues Journal of Cellular Biochemistry,51:426-435 (1993), short (1-100 μs) and longer (1-10 ms) pulses haveinduced electroporation in a variety of cell types. In a single cellmodel, most cells will exhibit electroporation in the range of 1-1.5Vapplied across the cell (membrane potential).

In addition, it is known in the art that macromolecules can be made tocross reversibly created pores at voltages of 120V or less applied tocells for durations of 20 microseconds to many milliseconds. Forapplications of electroporation to cell volumes, ranges of 10 V/cm to10,000 V/cm and pulse durations ranging from 1 nanosecond to 0.1 secondscan be applied. In one example, a relatively narrow (μsec) high voltage(200V) pulse can be followed by a longer (>mscc) lower voltage pulse(<100V). The first pulse or pulses open the pores and the second pulseor series of pulses assist in the movement of the BoNT-LC across thecell membrane and into the cell.

Certain factors affect how a delivered electric field will affect atargeted cell, including cell size, cell shape, cell orientation withrespect to the applied electric field, cell temperature, distancebetween cells (cell-cell separation), cell type, tissue heterogeneity,properties of the cellular membrane and the like.

Various waveforms or shapes of pulses may be applied to achieveelectroporation, including sinusoidal AC pulses, DC pulses, square wavepulses, exponentially decaying waveforms or other pulse shapes such ascombined AC/DC pulses, or DC shifted RF signals such as those describedby Chang in Cell Poration and Cell Fusion using an Oscillating ElectricField, Biophysical Journal October 1989, Volume 56 pgs 641-652,depending on the pulse generator used or the effect desired. Theparameters of applied energy may be varied, including all or some of thefollowing: waveform shape, amplitude, pulse duration, interval betweenpulses, number of pulses, combination of waveforms and the like.

There are at least two general power categories of medical ultrasoundwaves. One category of medical ultrasound wave is high acoustic pressureultrasound. Another category of medical ultrasound wave is low acousticpressure ultrasound.

Acoustic power is expressed in a variety of ways by those skilled in theart. One method of estimating the acoustic power of an acoustic wave ontissue is the Mechanical Index. The Mechanical Index (MI) is a standardmeasure of the acoustic output in an ultrasound system.

High acoustic pressure ultrasound systems generally have a MI greaterthan 10. Low acoustic pressure systems generally have a MI lower than 5.For example, diagnostic ultrasound systems are limited by law to aMechanical Index not to exceed 1.9.

Another measurement used by those skilled in the art is the spatialpeak, peak average intensity (Isppa). The intensity of an ultrasoundbeam is greater at the center of its cross section than at theperiphery. Similarly, the intensity varies over a given pulse ofultrasound energy. Isppa is measured at the location where intensity ismaximum averaged over the pulse duration. Isppa for high acousticpressure or high intensity focused ultrasound (HIFU) applications rangesfrom approximately 1500 W/cm2. to 9000 W/cm2. Diagnostic ultrasoundequipment, for instance, will generally have, and an Isppa less than 700W/cm2.

Yet another way in which ultrasound waves can be characterized is by theamplitude of their peak negative pressure. High acoustic pressure orHIFU applications employ waves with peak amplitudes in excess of 10 MPa.Low acoustic pressure ultrasound will generally have peak negativepressures in the range of 0.01 to 5.0 MPa. Diagnostic ultrasoundequipment, for example, will generally have a peak amplitude less than3.0 MPa.

Both high and low acoustic pressure ultrasound systems generally operatewithin the frequency range of 20 KHz-10.0 MHz Interventionalapplications (such as in blood vessels) operate clinically up to about50 MHz. Also ophthalmologic applications up to about 15 MHz. Diagnosticimaging typically uses frequencies of about 3 to about 10 MHz. Physicaltherapy ultrasound systems generally operate at frequencies of either1.0 MHz or 3.3 MHz.

High acoustic pressure ultrasound or high intensity focused ultrasoundhas been used for tissue disruption, for example for direct tumordestruction. High intensity focused ultrasound using high acousticpressure ultrasound is most commonly focused at a point in order toconcentrate the energy from the generated acoustic waves in a relativelysmall focus of tissue.

Systems for permeabilization of target tissue cell membranes may employeither high acoustic pressure or low acoustic pressure ultrasound. Someembodiments may preferably employ relatively low acoustic pressure, forexample the systems described herein where the transducers are mountedon the delivery devices and operate inside the body. Other systems mayoperate at interim acoustic pressure ranges. For example, systemsdescribed herein which employ an external ultrasound generator andtransducer and which conduct the ultrasound to the target tissuesthrough the use of a wave guide. In these systems, losses due totransduction through the wave guide can be compensated for by increasingthe input power to the wave guide until adequate power is delivered tothe target tissue. Finally, some systems described herein may employfocused or partially focused higher pressure ultrasound, for example thesystems which employ an external mask to conduct the ultrasonic powerthrough the tissues to the target tissues. It should be appreciated thatcombinations of high and low acoustic pressure systems may also beemployed.

It should also be appreciated that any embodiment employing ultrasonicenergy and ultrasound transducers can alternatively be configured as amicrowave energy system using microwave antennas. For example, theembodiments disclosed herein relating to delivering energy from anexternal mask equipped with ultrasound transducers can also beconfigured to deliver microwave energy using one or more microwaveantennas.

A schematic example of the methods of the present invention are shown inFIGS. 2A, 2B, 3A, 3B and 4 in a simplified single cell model. A targetedcell, e.g., an epithelial or goblet cell of the type which line thenasal cavity membrane, is shown in FIG. 2A. Fragmented neurotoxin suchas BoNT-LC (LC) is introduced into the vicinity of the targeted cell asdepicted in FIG. 2B. An energy field (EF) is applied in accordance withthe present invention resulting in the transfer of the BoNT-LC to theintracellular matrix (cytosol or cytoplasm) as shown in FIGS. 3A and 3B.Once this transfer has occurred, the release of acetylcholine from thepresynaptic neurons at the neuromuscular junctions of the epithelial orgoblet or other target cells is then blocked or disrupted. Once energyapplication is discontinued, the pores in the cell membrane recover orclose as depicted in FIG. 4.

The terms “poration” and “permeablization” will also cover forms ofcellular sonoporation. Just as pulses of high voltage electricity canopen transient pores in the cell membrane, ultrasonic energy can do thesame. See for example Guzman et al. “Equilibrium Loading of Cells withMacromolecules by Ultrasound: Effects of Molecular Sizing and AcousticEnergy”, Journal of Pharmaceutical Sciences, 91:7, 1693-1701, whichexamines the viability of ultrasound to deliver molecules of a varietyof sizes into target cells. In addition, techniques for nebulizingfluids and aqueous drugs are well known in the art, and as such, devicesof the present invention may be adapted to introduce a BoNT-LC solutionto a target region, such as the nasal passages and then effect selectivemembrane transport of the BoNT-LC into the cell using sonoporation.

To achieve the goals of the present invention, it may be desirable toemploy methods and apparatus for achieving cell membranepermeabilization via the application of an energy source, either from acatheter located directly in the vicinity of the targeted cells, or anexternally focused energy system. For purposes of this specification,the term “catheter” may be used to refer to an elongate element, hollowor solid, flexible or rigid and capable of percutaneous introduction toa body (either by itself, or through a separately created incision orpuncture), such as a sheath, a trocar, a needle, a lead. Furtherdescriptions of certain electroporation catheters are described in U.S.Provisional Patent Application No. 60/701,747 and Non-provisional patentapplication Ser. No. 11/459,582, the full disclosures of which areexpressly incorporated herein by reference.

FIGS. 5 and 5A-5B depict a system utilizing an electroporation catheterfor selective electroporation of targeted cells. In certainconfigurations of the present invention, voltages may be applied via theelectroporation catheter to induce reversible electroporation at thesame time as the catheter delivers the fragmented neurotoxin to thetargeted region.

Referring to FIG. 5, electroporation catheter system 20 comprises apulse generator 24 such as those generators available from CytopulseSciences, Inc. (Columbia, Md.) or the Gene Pulser Xcell (Bio-Rad, Inc.),or IGEA (Carpi, Italy), electrically connected to a catheter 22 having aproximal end and a distal region 26 adapted for minimally invasiveinsertion into the desired region of the body as described herein. Thecatheter further comprises an electroporation element 28 at the distalregion thereof. The electroporation element consists for example of afirst electrode 30 and a second electrode 32 operatively connected tothe pulse generator for delivering the desired number, duration,amplitude and frequency of pulses to affect the targeted cells. Theseparameters can be modified either by the system or the user, dependingon the location of the catheter within the body (intervening tissues orstructures), and the timing and duration of reversible cell porationdesired.

FIG. 5A depicts an arrangement of electrodes 30 and 32 that produces anelectric field concentrated in a lateral direction from the catheterbody whereas, FIG. 5B shows a device with electrodes 30 and 32configured to create a more uniform electric field about the shaft ofthe catheter body. Further catheter device and electrode configurationsare shown in FIGS. 6A-6D. FIG. 6A depicts an elongate catheter 40 havinga first and second electrode (42 and 44) near the distal tip thereof,and including a monitoring or stimulation electrode 46 in the vicinityof the active porating electrodes for localizing the treatment area. Insome embodiments, the monitoring or stimulating function may beperformed by one or more of the treatment electrodes. The catheterdevice may have an optional sharp tip 48 to facilitate percutaneousintroduction. FIG. 6B is a similar catheter device, but is furtheradapted to be steerable, or articulate at a region 53 near the distalend of the device. Such steering ability enables the operator tointroduce the device into tight or tortuous spaces (such as thebronchial passages, or cardiovascular vessels) so that optimal placementof electrodes 52, 54 and 56 of the device at the target location may beachieved.

FIG. 6C depicts a further embodiment of the catheter device describedabove, that includes an injection element such as needle 62 to allow forthe injection of a therapeutic agent such as a fragmented neurotoxinbefore, during or after the application of the pulsed energy orelectroporation. The injection element may be a needle as shown in FIG.6C, an infusion port, or other infusion means. Electrodes 64, 66 and 68are provided as discussed with respect to FIGS. 6A and 6B.

FIG. 6D depicts an alternative embodiment of the present invention,showing a catheter device 70 having electrode elements (72 and 74) thatare adapted to extend laterally from the main catheter body, and in somecases, penetrate the surrounding tissue prior to application of energy.In doing so the depth and direction of the energy field created by theelectroporative process, may be further controlled. A referenceelectrode 76 may also be provided.

FIG. 7 depicts an embodiment of the present invention utilizing anultrasonic element that may be particularly useful in delivery of theBoNT-LC to nasal tissue that provides a broad but targeted transport ofthe LC across the epithelial and goblet cell walls. In this device,ultrasound energy is delivered to the distal end 92 of the catheterdevice 90 via an ultrasonic waveguide that is operatively connected toan ultrasound energy source (U/SES) connected by cable 94. The LCfragment would be delivered from source 96 via the same lumen as thewaveguide, or via a separate lumen that exits the distal tip of thedevice. In operation, the ultrasonic energy would cause the LC solutionto be nebulized, forming mist clouds 98 within the lung, as shown inFIG. 8. The mist itself, in the appropriate concentrations, may act asan ultrasound coupler, conveying the ultrasonic energy to the wall ofthe lung or other targeted cellular structures, causing sonoporation ofthe targeted cells whereby the LC fragment is transmitted across thecell membranes to become an effective neurotransmitter blocker. In analternative embodiment, an ultrasonic transducer may be located directlyat the tip of the delivery device, eliminating the need for a waveguide. Various catheters useful for delivering vibrational energy totissue are described in U.S. Pat. Nos. 6,361,554 and 6,464,680 toBrisken, the contents of which are expressly incorporated herein byreference in their entirety, for various therapeutic effects, such asenhancing cellular absorption of a substance.

Any of the catheter devices described herein, or described in thecontemporaneously filed U.S. Provisional Patent Application No.60/701,747 and Non-provisional patent application Ser. No. 11/459,582,previously incorporated by reference in their entirety, may be adaptedto include an energy delivery element such as those described herein forpurposes of providing a membrane transport system for delivery of atoxin fragment of neurotoxin. In addition, certain catheter devices andmethods such as those set forth in U.S. Pat. Nos. 5,964,223 and6,526,976 to Baran may be adapted to include energy transmissionelements capable of producing a porative effect at the cellular level,including electrodes, ultrasonic elements and the like, for treatment inthe nasal passages.

Furthermore, any of the foregoing systems may include electrodes orother monitoring systems either located on the treatment catheter, orexternal to the patient, to determine the degree of treatment to theregion, including, thermocouple, ultrasound transducers, fiberoptics,sensing or stimulating electrodes. Further, it may be desirable toincorporate multiple pairs of electrodes that may be activated in pairs,in groups, or in a sequential manner in order to maximize the desiredshape of the energy field (EF) while minimizing the field strengthrequirements.

It is within the scope of the present invention to deliver the toxin,the energy, or both, non-invasively. For example, as illustrated in FIG.9, the patient may draw the toxin into the nasal cavity from a hand-helddispersion device DD. After a sufficient amount of the toxin has beeninfused into the nasal cavity, a separate hand-held transducer TDconnected to an appropriate power supply PS will be energized andapplied to the nasal cavities by passing the transducer over theappropriate regions of the forehead and nose. Optionally, the transducercan have a focused output so that the acoustic energy is focused in anappropriate depth beneath the skin surface. Typically, from about 0.1 cmto 2 cm.

While the toxins and porating energy of the present invention may bedelivered to the nasal cavity in a variety of ways, the followingprovides a number of specific examples of catheters and other structuresfor delivering toxins to preselected portions of the nasal cavity. Forexample, as shown in FIG. 10, a balloon catheter 100 may be providedwith a porous balloon 102 at its distal end. The balloon would be porousover at least a portion of its body so that solution delivered toinflate the balloon, which would contain desired levels of the toxin ortoxin fragment, would release the solution through the balloon at acontrolled rate. By further providing one or more ultrasonic transducers104 within the balloon, optionally mounted on the catheter body,ultrasonic poration energy can be delivered to the adjacent nasalmembranes which are receiving the toxin solution. As illustrated in FIG.10, the toxin is being delivered to a lower surface of the inferiormeatus IM to localize and enhance cellular delivery at the balloontissue interface. Alternatively, the balloon could carry the toxin in areleasable form over its exterior surface in order to deliver to anyadjacent tissue structure. In some instances, the toxin could be carriedor encapsulated in delivery vesicles which are preferentially fracturedby the same acoustic energy which permeablizes the cell wall. Othercoatings include hydrogels, such as those produced by Surmodics, Inc.,BioCoat, Inc., or the like. In some instances, it may be desirable toprovide a coupling agent over and/or within the balloon in order toenhance the delivery of ultrasonic energy from the internal transducer.In still other instances, it would be possible to place polymerictransducers on or within the balloon surface in order to directlydeliver ultrasonic or other acoustic energy into the adjacent tissues.

In all the above cases, the ultrasonic transducers can be configured inorder to selectively deliver the energy to desired portions of theadjacent tissues. For example, in the embodiment of FIG. 10, theinternal transducers 104 can be configured to focus the ultrasonicenergy generally upwardly (as viewed in FIG. 10) in order topreferentially deliver the toxins into the inferior meatus IM whileminimizing delivery elsewhere.

As a further option, the balloon could be inflated by a coupling agentin order to enhance the transmission of the ultrasonic or other acousticenergy, while the toxin solution could be infused into the treatmentarea before or simultaneously using either a separate lumen in thecatheter or a separate tube or other delivery catheter. In this way, itwould not be necessary to inflate the balloon with a relatively largevolume of the toxin solution.

The balloon catheters can be introduced by any conventional technique,for example, in some instances, it may be desirable to use a guidewireto place the catheter into a desired sinus or other location, optionallyusing fluoroscopic, MM or ultrasound imaging.

Referring now to FIG. 11, a front view of particular balloons placed asgenerally shown in FIG. 10, is shown in more detail. A single balloon102 can be around the structures H in the inferior meatus.Alternatively, a pair of balloon structures 103 may be placed in thesame space, as shown in the right hand portion of FIG. 11. Optionally,the balloons could be formed from an elastic material, such as asilicone, urethane, latex, thermoplastic elastomers, or other materialswhere the material is treated to be appropriately porous, for example bylaser drilling. Alternatively, the balloons could be formed fromnon-distensible materials which are pre-formed to conform to the desiredtarget cavities. The non-distensible balloons could also be laserdrilled or otherwise made permeable in order to release the toxinsolutions of the present invention. Alternatively, either type ofballoon could be coated with the toxin solutions, coupling solutions, orother materials which are useful in the protocols of the presentinvention.

Referring now to FIGS. 12A. 12B, and 12C, as an alternative toinflatable balloons, toxin delivery structures may be made to be variousshapes, for example a generally “flattened” balloons 102, whose profileis narrower in one axis than the other, for example by placement of aninternal nitinol or other elastic frame or scaffold, or a stainlesssteel wire 103 that is fed into the balloon outer structure to form suchshape, within a suitable porous cover or membrane. Thus, the structure120 may be expanded by the scaffold 122 after release from a deliverytube 124. The structures can be used to deliver energy and/or toxin inany of the ways described previously with respect to balloons, includingby carrying a transducer or electrode on or within the structure anddelivering a toxin solution from the interior of the self-expandingstructure through a porous portion of the structure wall.

In some instances, it will be desirable to protect the olfactory bulb ofthe sinuses from treatment with the toxin solutions of the presentinvention. Referring now to FIGS. 13 and 14, the porous portion of adelivery balloon 102 can be positioned so that the remaining non-poroussegment is in contact with the olfactory bulb (FIG. 13). Thus, when theballoon is inflated and the toxin solution delivered, it will not bedirected at the tissues of the olfactory bulb (OB).

As shown in FIG. 14, which is a cross-sectional view of FIG. 13, insteadof rendering the top portion of the delivery balloon non-porous, itwould be possible to simply refrain from filling the top portion withthe toxin solution and/or a coupling solution. This can be achieved byfilling the balloon with a known volume of air 111 in addition to thetoxin solution. With the patient positioned appropriately, the air willfill the portion of the balloon in proximity to the olfactory bulb,excluding this tissue from toxin contact. Additionally, the air bubblemay act as an ultrasound insulator to inhibit energy delivery to thenon-targeted or protected tissue. Thus, delivery of the toxin to theregion around the olfactory bulb and/or delivery of the energy to theregion around the olfactory bulb can be partially or wholly prevented.

Referring now to FIGS. 15 and 16, the balloon may be sized andpositioned to target an area of high epithelial or goblet cell (G)concentration, for example in the back of the nasal passages in the areaof the nasopharynx. By targeting this area of the nasal membrane, a highpercentage of mucus-secreting epithelial or goblet cells can be treatedwith a device which is relatively small and which may carry a relativelylow infusion volume and require less energy. Moreover, the olfactorybulb is inherently protected with this technique since the balloon ispositioned well away from that area. If desired, of course, additionalshielding, shaping or other protective balloons could be positionedbetween the olfactory bulb and the toxin and energy deliveringcomponents of the present invention.

As shown in FIG. 17, direct infusion and treatment of particular sinusesmay be effected using relatively small occlusion balloons 102 whichocclude and isolate natural openings into those sinuses. Once theballoon is in place and the occlusion balloon employed, the toxicsolution can be delivered by infusion, dispersion, or other conventionaltechniques. Once the toxin solution is present in the sinus, all or aportion of the membrane of the sinus can then be treated with anexternal or other ultrasonic source.

For example, as shown in FIGS. 18 and 19, the external transducer maycomprise a mask which conforms to the nose and optionally over thesinuses, where the mask carries one or more ultrasonic or other acoustictransducers (TD) adapted to deliver energy transcutaneously into thesinuses. The mask may comprise a plurality of individual transducers(TD), which may be made from one, two, or several generally continuouspiezoelectric films which are formed over or lamented within the mask.Alternatively, multiple individual piezoelectric crystal transducers canbe built into the mask.

The effect of such externally applied ultrasonic energy can be enhancedby introducing microbubbles (free air) into the isolated sinuses and/ornasal passages which have been filled with toxin solution. For example,encapsulated microbubbles, which are generally useful asechocardiographic contrast agents, or specialty perfluorocarbons, areuseful as such ultrasonic enhancing agents. By encapsulating the toxinmolecules in spheres or bubbles, or by simply placing the spheres orbubbles in proximity to toxin molecules, the ultrasonic or otheracoustic energy can be captured and stored until it is abruptly releasedwith fracture of the sphere or bubble. Such microspheres will also actas resonance bodies as defined below.

Referring now to FIGS. 20 and 21, a catheter 40 is placed at theposterior outlet of the nasal passages in the region of the nasopharynx.The catheters configured to occlude outflow from these sinuses andpassages into the throat. As shown in FIG. 20, a balloon catheter 102 orother occlusion device could be configured to block such passage. Asshown in FIG. 20, the catheter is delivered in through the mouth andguided into the posterior portion of the nasal cavities, typically usinga guidewire. Once the nasopharynx of the posterior portion of the nasalcavity is occluded, toxin solution (BoNT) can be infused through theoccluding catheter lumen, or through a separate infusion catheter ortube, in order to treat substantially the entire sinus and/or nasalcavity membrane at once (FIG. 21). When the toxin solution is introducedthrough the catheter at the posterior region of the cavities, it willfrequently be desirable to occlude the nostrils, for example using anasal clip 105.

As shown in FIGS. 22 and 23, specially designed nose plugs 105 can beprovided with air bleed valves 106 which are used to occlude thenostrils in order to evacuate or bleed air from the nasal passages whilefilling the passages with the toxin solution. The nose plugs 105 couldoptionally include ultrasonic transducers in order to deliver ultrasonicor other acoustic energy into the solutions entrapped within the nasalcavities using the nostril plugs. Alternatively, of course, theultrasound or other acoustic energy could be delivered from an externaltransducer as described previously.

Referring now to FIGS. 24 and 25, an alternate occlusion catheter systemfor nasopharynx occlusion is illustrated. An occlusion catheter 40 isintroduced through a nostril, where the tip includes an ultrasonictransducer to provide sonoporation. A nostril plug 105 is providedproximally on the shaft of the catheter, while the cavity is blockedwith a separate occlusion balloon 102 introduced through the mouth andinto the posterior nasopharynx region. The toxin solution can beintroduced into the cavity through either the catheters which passthrough or reside in the nostrils or the catheter which occludes theposterior nasopharynx.

FIGS. 26 and 27 illustrate how a catheter 40 with side holes 108 can beconfigured to deliver toxin away from the olfactory bulb, even when usedalone without separate nasopharynx occlusion catheters. The catheterspreferably carry an occlusion balloon or other structure near theirdistal ends 107 to prevent or inhibit toxin from reaching the olfactorybulb

Use of these or other catheter devices can deliver toxin incorporatedinto vesicles which may be configured as “resonance” bodies, whichreduce the need to fill the nasal cavities with a liquid or other formof toxin. For example, lipid microspheres which incorporate the toxinmay be sprayed or aerosolized onto target surfaces of the nasalepithelium. After the lipid or other resonance bodies are attached tothe targeted epithelium membrane surface(s), the ultrasound energy canbe delivered from the catheter or externally through the skin in orderto selectively porate the epithelial or goblet cells to enhanceintroduction of the toxin vis-à-vis resonance bodies. A protectiondevice at the end of the shaft can be provided to shield the olfactorybulb from the toxin.

Referring to FIG. 29, the toxin may be delivered as a conventional nasalspray (BoNT), as mentioned hereinbefore, and the poration energy can bedelivered through a face mask. The poration energy might alternativelybe delivered as ultrasound energy delivered through a mist, withoutdirect contact to the tissues. This mist might be the same mist whichcontains the toxin, or it might be a different, possibly denser mistdelivered at some time after the toxin has been delivered. The deliverydevices for these mists might be introduced a relatively short distanceinto the nose. Thus the entire therapy might comprise the specializeddelivery of two mists.

Referring now to FIGS. 28 and 30, an infusion catheter 40 can be engagedagainst the ostium of a sinus cavity (FIG. 28). A guidewire 110 may thenbe advanced through the infusion catheter and into the sinus cavity(FIG. 30). The guidewire can be formed as a wave guide to deliverultrasonic energy, as an electrode to deliver electroporation energy, oras an infusion wire to deliver the toxin solution itself. The wire couldfurther be configured to perform two or more of these functions. Thecatheter could be configured to act as a counter electrode when theguidewire is acting as an electroporation electrode in bipolar energydelivery.

Referring now to FIG. 31, the catheter advanced to the os of a sinuscavity, as illustrated, can also be used to deliver a helical orrandomly shaped delivery tube 112 which is deployed within the sinus.Preferably, the tube will expand to engage a major portion of the wallof the sinus cavity. Alternatively, the geometry could be selected toselectively engage only a particular portion of the wall of the sinuscavity. The wire can further be adapted to deliver energy, eitherelectrical or acoustic, and/or may be configured to deliver anddistribute the toxin solution within the cavity. In still otherconfigurations, the wire could be coated to deliver the agent to thewall, and still further the wire could deliver ultrasound gels, saline,degassed water, or the like, to enhance coupling of a separateultrasonic energy source.

Referring now to FIG. 32, two or more deployment catheters can be usedto advance any of the guidewires or other wire structures discussedabove. As illustrated in FIG. 32, an electrode basket 113 may bedeployed through the delivery catheter. Alternatively, a multiply tinedcatheter 114 structure may be delivered through the delivery catheter.

FIGS. 33 and 34 illustrate a device for applying BoNT to the treatmentarea within the nasal cavity. This device comprises a handle 115 havinga proximal section, a body and a distal section. The body of the handlecomprises a first member 116 and a second member 117. The first memberand second member merge at the proximal section and terminate at thedistal section, wherein the distal section comprises a first end andsecond end corresponding to the first member and second member. Thedevice further comprises applicator tips 118 connected to each of thefirst end and second, wherein the applicator tips are configured forinsertion into the nasal passageway, as shown in FIG. 35.

Once within the nasal cavity, the applicator tips 117 and 118 can applyBoNT to the nasal passageway and, specifically, the turbinates along thenasal wall. The BoNT can be applied or affixed to the applicator tips asa liquid solution, gel, foam, cream, lotion and/or a lyophilizedcompound prior to being positioned within the nasal passageway.Alternatively, as illustrated in FIG. 36, the handle can be configuredwith an infusion channel 119 for delivering the BoNT to the applicatortips following placement in the nasal passageway. In this configuration,the handle may further comprise an access port at its proximal sectionthat is in fluid communication with a BoNT source.

As shown in FIG. 33, the loop member may be configured to provide anoutward lateral force such that the applicator tips 118 are firmlycontacted against the nasal turbinates when placed in the nasalpassageway. With reference to FIG. 37A, the operator would apply inwardpressure in the direction of the arrows to the handle to achieve acompressed configuration, as shown in FIG. 37C, prior to inserting theapplicator tips into the nose. Once the applicator tips of the deviceare properly inserted into the nasal passageway, this pressure would bereleased such that the outward bias in the handle transitions the handlefrom a compressed configuration to an expanded configuration, as shownin FIG. 37B, wherein the applicator tips are pressed against the nasalturbinates. The applicator tips can be held against the turbinates bythe outward bias for sufficient time to allow a therapeuticallyeffective amount of BoNT to be absorbed by the nasal cavity wall.

This outward bias may be achieved by spring loading the device 120.Specifically, the handle itself may comprise a spring element, whereinthe handle is dimensioned and configured with a residual spring forcethat exhibits this outward bias. Additionally or alternatively, thehandle may comprise a material with mechanical properties to facilitatethe spring action with little to no inelastic deformation resulting fromthe inward pressure applied by the operator. For example, at least aportion of the proximal section of the handle may comprise spring steel,stainless steel, nitinol, or MP35N alloy. Alternatively, as illustratedin FIG. 38, a spring element 120 that is separate from the handle may beused to apply outward lateral pressure to the first and second membersof the handle body.

To facilitate the insertion of the tip applicator through the nostriland into the nasal passageway, it may be desirable for the applicatortip to initially have a low volume configuration. Once properlypositioned in the nasal passageway, it would be desirable for theapplicator to have an expanded volume configuration for maximizingcontact with the nasal turbinates. In one exemplary embodiment, the tipapplicator may comprise a sponge such that the sponge 121 is in a lowvolume configuration when dry (FIG. 39A) and an expanded configurationwhen wet (FIG. 39B), wherein the sponge 121 is configured to fitsecurely within the nasal passageway.

In the embodiment illustrated in FIGS. 39A and 39B, the dry spongeapplicator could be preloaded with lyophilized BoNT and wetted with aliquid (e.g., saline) following placement of the applicator in the nasalpassageway. The liquid can be introduced into the nasal passageway usinga spray or a catheter, or the BoNT may simply be rewetted by the nasalsecretions themselves. Alternatively, as described with respect to FIG.36, the liquid can be infused into the applicator tip through a channel119 in the device handle. Still alternatively, the liquid infusedthrough the channel can be a solution comprising BoNT, therebyeliminating the need for the dry sponge applicator to be preloaded withBoNT.

To facilitate the expansion of the applicator tip, thereby maximizingthe surface contact between the nasal cavity wall and applicator tip, itmay be desirable to incorporate a spring element 122 within theapplicator tip 118. The embodiment in FIGS. 40A and 40B shows anapplicator tip comprising a sponge 121 and a spring element 122 in anexpanded and compressed configuration. This configuration can be usedinstead of or in addition to the wet/dry sponge embodiment discussedabove.

The spring element may comprise any type of compressible spring and anynumber of elastically deformable polymers or metals, including, springsteel, stainless steel, nitinol, and MP35N alloy. As shown in many ofthe above embodiments, the spring element may comprise a v-shape spring.Alternatively, the spring element may comprise a closed-loop spring 123,as illustrated in FIG. 41.

For embodiments utilizing a spring-loaded applicator tip, it will benecessary to hold the spring 122 in its compressed state until it isproperly positioned within the nasal cavity, at which time the springcan be released to allow the applicator to expand into the nasal cavity.In the wet/dry sponge 121 embodiment described with respect to FIGS. 39Aand 39B, a sponge and spring can be selected and matched such that thestiffness of the dry sponge is sufficient to overcome the springstiffness and hold the spring in a compressed configuration until itbecomes wet.

In another embodiment employing a spring-loaded applicator tip, anactuator can be used to hold the spring in a compressed state. FIG. 42illustrates a spring-loaded applicator tip 124 that is restrained in acompressed state by a slidably-engaged actuator 125. Theslidably-engaged actuator may comprise a retractable sheath or collar126 for holding the spring in its compressed configuration. Once theapplicator is positioned within the nasal cavity, the actuator can beretracted to release the spring, thereby expanding the applicator.

The device may optionally comprise an engagement element 127 forengaging and retracting the actuators on both applicators. FIG. 43 showsa device comprising a handle 115, two actuator-equipped applicator tips124 and an engagement element 127 in contact with each applicator tipactuator 124. The engagement element is configured for movement alongthe longitudinal axis of the handle, wherein such movement may engage orretract the actuator resulting in compression or expansion of thespring-loaded applicator tip, respectively.

It may be desirable for the spring-assisted expansion of the applicatortip to be directionally biased to maximize contact with the wall of thenasal cavity and optimize contact pressure with the nasal turbinates.For example, the spring element can be dimensioned and configured suchthat the applicator expands laterally towards the turbinates of thenasal cavity. Alternatively or additionally, portions of the applicatortip may comprise an impermeable lining such that delivery of BoNT tocertain portions of the nasal cavity is optimized and undesirablemigration of BoNT solution is minimized.

Although toxins can be administered to the body to achieve a therapeuticbenefit, the same toxins can cause local and systematic damage tonon-targeted body tissues. Accordingly, it would also be desirable forthe apparatus to be configured such that only the amount of toxinnecessary to treat the nasal cavity is loaded on the applicator tip andapplied to the nasal wall. It this embodiment, it would be desirable forthe applicator to carry a predetermined quantity of toxin, wherein thepredetermined quantity is the amount necessary to provide a therapeuticeffect. It would also be desirable for the applicator to be configuredsuch that most, if not all, of the toxin carried on the applicator isdelivered to the nasal wall, wherein little to no toxin runs, escapes ormigrates to non-target portions of body tissue.

Additionally, it would be desirable for the applicator to be configuredto provide a controlled delivery of toxin to facilitate absorption ofthe toxin into the walls of the nasal cavity. An applicator providing acontrolled delivery of toxin can be configured such that the rate oftoxin delivery is proportionate with the rate of BoNT absorption acrossthe nasal membrane. Such a controlled delivery will ensure that thetoxin is absorbed into the nasal tissue and not dispersed elsewhere inthe body.

An apparatus for treating a nasal cavity of a patient via a controlledand uniform delivery of BoNT may comprise an applicator having an innermember, an outer member and an impermeable lining, wherein theimpermeable lining separates the inner member and outer member. In thisembodiment, the outer member serves as a carrier for a toxin (e.g.,BoNT). The outer member may comprise any material or structure forcarrying BoNT such as an open cell foam (e.g., sponge), mesh pad, porousor perforated balloon, polymeric sheet having microchannels,bioresorbable coating or muco-adhesive surface having wells oropen-faced chambers. The outer member may also comprise an array ofmicroneedles to facilitate the passage of BoNT across the nasalmembrane. The inner member is configured for occupying space when theapplicator is positioned within the nasal cavity such that the outermember is placed in contact with the wall of the nasal cavity. The innermember may be any compliant material such as a sponge, balloon or foamrubber. The impermeable lining (e.g., tetrafluoroethylene) prevents theBoNT from retreating from the outer member to inner member and,accordingly, facilitates the transfer of BoNT from the applicator to thetissue of the nasal wall. As with applicator embodiments that have beenpreviously discussed herein, the outer member can be pre soaked orfilled with BoNT solution, infused with BoNT following placement in thenasal passageway, or pre-loaded with freeze-dried BoNT that can bereconstituted with infused saline.

In one embodiment, both the inner and outer members may compriseballoons, wherein the BoNT is carried in the space between the inner andouter balloons. The outer balloon can be a perforated polymer (e.g.,polyethylene terephthalate or expanded polytetrafluoroethylene) forreleasing BoNT in a controlled and uniform matter. The inner member canbe a compliant balloon, wherein the volume occupied by the inner ballooncan be adjusted by injecting a fluid (e.g., air or saline) into theinner balloon. In this configuration, the impermeable lining iscomprised of the wall of the inner balloon and the applicator's BoNTcarrying capacity is based on the volume of the outer balloon relativeto that of the inner balloon. For example, an applicator could beconfigured to carry less BoNT by increasing the inner balloon's volumerelative to the outer balloon's volume.

In a preferred embodiment, the inner member comprises (1) a low volumeconfiguration to facilitate the applicator's insertion into andplacement within the nasal passageway and (2) an expanded volumeconfiguration for pressing the outer member against the walls of thenasal cavity. The expansion of the inner member relative to the outermember can also facilitate the controlled release of BoNT from the outermember. Once the applicator is in its expanded volume configuration,additional fluid can be infused into the inner member to reduce thevolume of the outer member relative to the inner member, thereby forcingthe BoNT from the outer member. In fact, the expansion of the innermember may be configured such that the resulting stretching andcompression of the outer member causes a controlled release of BoNT fromthe outer member, wherein the rate of BoNT release is proportional tothe inner member's rate of expansion. In the embodiment comprising aninner balloon and outer balloon, the expansion of the inner member canbe facilitated by the introduction of fluid into the inner member. Inother embodiments, the expansion of the inner member can be facilitatedby a spring member.

In any of the embodiments discussed herein, it may be desirable to adaptthe applicator to the geometry of the nasal cavity. For example, inembodiments comprising an outer member and inner member, the outermember can be configured to match the shape of the nasal cavity orportions of the nasal passageway following the expansion of the innermember. By achieving better contact, the delivery of toxin to and acrossthe nasal membrane can be optimized.

To achieve a more focal treatment, the applicator tip can be equippedwith a muco-adhesive pad that is pre-loaded with BoNT solution ratherthan a sponge. This pad can be configured to optimize the delivery ofBoNT to the mucosa. Alternatively, the applicator tip may furthercomprise a bioabsorbable coating or film carrying BoNT. In thisembodiment, the applicator tip may comprise a BoNT-loaded bioresorbablepolymer that can be absorbed into the nasal cavity tissue. The tip canbe configured such that the BoNT can be delivered to the nasal wall bothimmediately and as the coating is absorbed into the tissue.

Similar to the other devices discussed in this application, the devicedescribed with respect to FIGS. 33 and 34 can be used to deliver BoNT-LCto the nasal cavity instead of the BoNT intact molecule. In cases wherethis device is used to deliver BoNT-LC to the nasal cavity, any of thepreviously-described, energy-based delivery systems can be used to causeporation in the nasal tissue to facilitate delivery of the BoNT-LC tothe tissue. Additionally or alternatively, this device can be equippedwith an energy delivery element for causing poration in the targettissue in conjunction with delivery of BoNT-LC to the target tissue. Forexample, the device may comprise an electrode, antenna or ultrasonictransducer that is electrically connected to an energy generatorconfigured for delivering energy via the energy delivery element to thetarget tissue at a voltage, amplitude, frequency, etc. sufficient tocause poration or permeablization in the target tissue.

Throughout this disclosure, the LC solution has typically been referredto as an infused, aerosolized or sprayed liquid. LC incorporated intocoatings on devices has also been described. It should be noted,however, that other forms of LC delivery may be desirable.

For instance, commercially available botulinum toxins (such asBotox™—Allergan) are supplied as a dry lyophilized powder, and must bereconstituted prior to delivery by the addition of saline to thepackaging vial. Similarly, light chain would be most readily availableand stable in a powdered form. It may be desirable to spray or blow thepowdered form of the LC into the target airways directly, without anyreconstitution by liquid.

The lyophilized powder could also be formed into sheets, ribbons,pellets microspheres, or any other desirable form, and introduced to thetarget tissues.

Instead of a saline or low viscosity carrier, it may be desirable todeliver the light chain in a gel carrier, such as the types of gelswhich are commonly used for ultrasound coupling. Other appropriate gelcarriers include such biocompatible gels as hyaluronic acid (HA). HA hasthe added benefit of being a thixotropic liquid—its viscosity drops asit begins to flow or as increasing shear stress is applied, and thenreturns to a higher viscosity state as it comes to rest. This would aidin delivery of the solution through catheters and the like, whileallowing the gel to remain in place once delivered. HA is also extremelybiocompatible, and would allow efficient ultrasonic coupling to thetarget tissues. The application of ultrasonic energy might also reducethe viscosity of the HA gel, possibly improving the delivery of toxininto the tissues.

It may also be desirable to incorporate the light chain into a foam, orto foam the LC solution upon or during delivery of the LC to the targettissues. Foams may better fill the entire targeted airway, and may trapwater or coupling agents to allow efficient ultrasonic coupling. In afurther embodiment, the foam may be energized within or as it exits thecatheter shaft to further enhance the delivery of the LC to cells thatare contacted by the energized foam and LC foam solution.

In addition to BTX-LC, it may be desirable to deliver additional agentsto the nasal passages and sinuses prior to, coincident with, or afterdeliver of the LC. Adjunctive therapies may include agents designed toslow down or halt the motion of the cilia, in order to aid in deliveryof the LC to the target tissues by prevention of their mobilization bythe cilia. Agents known to slow or halt the motion of cilia include butare not limited to epinephrine dilutions of 1:1000 (which causes ciliarydeath), 1:10,000 (which causes reversible paralysis), 10% cocaine(induces paralysis) or 2.5% cocaine (slows or stops cilia).

Other adjunctive therapies may include the use of or pretreatment withmucolytics, which will thin mucus secretions within the nose and mayallow better penetration of LC into the target cells.

Decongestants such as epinephrine also cause constriction of thevasculature in the nasal passages, which in addition to temporarilyreducing swelling of the target tissues, may decrease the risks of LCentering the blood stream during poration and delivery. Epinephrine alsoconstricts the blood vessels locally, which may increase the residencetime of other locally delivered agents or decrease their likelihood ofentering systemic circulation.

Steroids may be used to reduce swelling and inflammation prior to LCtreatment in order to improve LC delivery to target tissues. In theabovementioned embodiments, it may be important to note that by far themost significant effects will be seen in areas where both the LC and thepermeablizing energy are delivered. Therefore, although it may be bestto deliver both LC and energy to substantially the same area, forreasons of anatomy, ease of delivery, etc., either the LC or the energymight be delivered more broadly, or to a somewhat different area. As anextreme example, the LC might be delivered systemically or to the entirerespiratory pathway, followed by very localized delivery of energy tothe desired area. Alternatively, the LC could be delivered to a specificsinus, followed by energy to the entire nose and sinus using astandardized external energy delivery mask.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

What is claimed is:
 1. A method for treating a nasal condition in apatient, said method comprising: inserting an applicator tip of anapparatus through a nostril of the patient and into a nasal cavity ofthe patient, wherein the applicator tip comprises an inner expandablemember and an outer expandable member extending around the innerexpandable member, wherein the inner expandable member is expanded inthe nasal cavity thereby causing the outer expandable member to expandand contact a wall of the nasal cavity, and wherein a toxin is deliveredfrom the expanded outer expandable member to target cells in the wall ofthe nasal cavity.
 2. The method of claim 1, wherein the toxin comprisesa light chain fragment of a neurotoxin substantially free of heavy chainfragments of the neurotoxin.
 3. The method of claim 2, wherein theneurotoxin consists of botulinum toxin.
 4. The method of claim 3,wherein the light chain fragment is derived from at least one ofbotulinum toxins A, B, C, D, E, F, and G.
 5. The method of claim 1,wherein the inner expandable member is disposed within the outerexpandable member.
 6. The method of claim 5, wherein the toxin iseither: (i) carried by the outer expandable member or (ii) disposed in aspace between the outer and inner expandable members.
 7. The method ofclaim 1, wherein the outer expandable member comprises an outer balloonand the toxin is delivered by passing the toxin through one or morepores of the outer balloon.
 8. The method of claim 7, wherein the innerexpandable member comprises an inner balloon.
 9. The method of claim 8,wherein the inner expandable member is expanded by filling the innerballoon with a fluid.
 10. The method of claim 1, further comprisingapplying energy to the target cells to enhance delivery of the toxin tothe target cells.
 11. The method of claim 10, wherein applying energy tothe target cells comprises porating cell membranes of the target cells.12. The method of claim 1, wherein the inner expandable membersubstantially fills the nasal cavity when expanded, thereby inhibitingrelease of the toxin into portions of the nasal cavity other than thewall.
 13. The method of claim 12, wherein the toxin is delivered bydelivering a therapeutic dose to the wall of the nasal cavity whileinhibiting release of the toxin into other portions of the nasal cavity.14. The method of claim 1, wherein the apparatus further comprises ahandle and at least one member connected to the handle, wherein thehandle has a compressed configuration and an expanded configuration, andwherein the at least one member comprises the applicator tip.
 15. Themethod of claim 14, wherein the applicator tip is inserted into thenasal cavity with the handle in the compressed configuration.
 16. Themethod of claim 14, wherein the handle is biased to be in the expandedconfiguration such that when the applicator tip is inserted into thenasal cavity, the applicator tip is pressed against a nasal turbinate ofthe nasal cavity.
 17. The method of claim 14, wherein the at least onemember comprises a first member and a second member, the first membercomprising a first applicator tip and the second member comprising asecond applicator tip.
 18. The method of claim 17, wherein inserting theapplicator tip comprises inserting the first applicator tip through afirst nostril of the patient and inserting the second applicator tipthrough a second nostril of the patient.
 19. The method of claim 1,wherein the inner expandable member comprises a spring element.
 20. Themethod of claim 1, wherein the outer expandable member comprises a drysponge.
 21. The method of claim 1, wherein the applicator tip carries apredetermined amount of the toxin necessary to provide a therapeuticeffect.
 22. The method of claim 1, wherein the toxin is delivered at arate proportionate with a rate of toxin absorption across a nasalmembrane of the patient.
 23. The method of claim 1, wherein the outerexpandable member when expanded is configured to match a shape of atleast a portion of the nasal cavity.
 24. A method for treating a nasalcondition in a patient, said method comprising: inserting a firstapplicator tip and a second applicator tip of an apparatus respectivelythrough a first nostril and a second nostril of the patient and into anasal cavity of the patient with a handle of the apparatus, wherein thefirst applicator tip and the second applicator tip each comprise aninner expandable member and an outer expandable member extending aroundthe inner expandable member, wherein the inner expandable members areexpanded in the nasal cavity thereby causing the outer expandable memberto expand and contact a wall of the nasal cavity, and wherein a toxin isdelivered from the expanded outer expandable members to target cells inthe wall of the nasal cavity.